When active substances are encapsulated in drug delivery systems, their bioavailability and therapeutic index is improved over an extended period of time. A drug delivery system including polymer microspheres has been developed for injection, implants, transdermal patches, and aerosols. Polymeric microspheres have a variety of uses in the medical and industrial areas since they provide a large surface area, can be easily injected, and do not require removal after completion of drug release.
Method for producing microspheres include single and double emulsion solvent evaporation, spray drying, phase separation, simple and complex coacervation, and interfacial polymerization. However, most methods generate microspheres having a wide size distribution with little or no control over the average diameter. Control of sphere size and size distribution are the ultimate goals of drug delivery. A particular release rate and a desired route of administration typically require a particular sphere size. Using filters is a possibility, but the use of filter results in a waste of expensive material. Therefore, several methods that allow control over particle size and size distribution have been proposed. Each of these methods has drawbacks that prevent the use of microspheres in various application.
Proposed methods include high shear emulsification which generates microspheres of average diameter not higher than 25 μm but many application require a greater size. This method also applies temperature restrictions on the solutions that can be used. Thus, the method cannot be used for polymers with low melting temperature, like many polylactide-co-glycolides (PLGAs) or for encapsulating temperature-sensitive drugs, like proteins.
Monomer polymerization techniques are not appropriate for drug encapsulation due to harsh chemical and/or physical environments that can denaturate drugs. In addition, some of these methods lead to formation of microspheres with diameters not grater than 3.5 μm.
An electrostatically controlled extrusion method is not capable of generating uniformly-sized microspheres.
In a porous membrane method, only low viscosity polymers can be used. Even if the polymer solution is of low viscosity, addition of a drug can increase the overall viscosity, thus limiting not just the range/concentrations of the polymers that can be used, but also the drug loading concentrations.
Injection methods do not demonstrate control over average diameter through manipulation of process parameters. Moreover, such methods have the disadvantage of not being able to produce microspheres of narrow size distributions.
A vibratory excitation process is based on continuous mode jetting in which a flow of polymer exits a piezoelectric orifice and a small perturbation applied to the flow breaks the jet into small drops. This method requires low voltages and high frequencies to be applied to the piezoelectric (PZT) device, as well as significant pressure to the polymer solution. Under this pressure, only high quantities of expensive fluid can be jetted.
A need has thus arisen for a simple and controllable manufacturing method for forming uniformly-sized polymer microspheres.